tbuckley/cabot-search huggingface dataset:
Paxalisib in patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status: Final phase 2 study results.
Authors: Patrick Y. Wen, John Frederick de Groot, James Battiste, Samuel A. Goldlust, James Stuart Garner, John Friend, Jeremy Andrew Simpson, Denise Damek, Alan Olivero, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2022)

2047 Background: Paxalisib, a potent oral selective brain-penetrant small molecule PI3K/mTOR inhibitor, has shown activity in nonclinical brain cancer models and promising phase 1 data in progressive / recurrent high-grade gliomas (NCT01547546). This multicenter phase 2 progressive design trial (NCT03522298) aimed to establish the maximum tolerated dose (MTD) for once-daily (QD) dosing, and to evaluate safety, tolerability, pharmacokinetics (PK), and clinical activity of paxalisib in patients with newly diagnosed glioblastoma and unmethylated MGMT promotor status. Methods: Eligible patients were males or females, aged ≥18 years, who had undergone surgical resection and chemoradiotherapy (Stupp Regimen), and were considered to be progression free before starting adjuvant paxalisib. Stage 1 used a standard 3+3 dose-escalation design to determine the MTD in this population. Stage 2 was a two-arm, open-label, expansion cohort with patients randomized 1:1 to receive paxalisib at the MTD under fed or fasted conditions. In both stages, treatment comprised daily paxalisib administered in 28-day cycles, continuously until disease progression or unacceptable toxicity. Efficacy analyses are based on investigator review and from date of diagnosis. Results: Patients (n = 30; 70.0% males, 83.3% white, mean age 58.5 years) had a mean time since diagnosis of 3.75 months. The majority (n = 29) received between 1 and 6 treatment cycles and one received 29 cycles. In Stage 1 (n = 9), an MTD of 60mg was established on the dose-limiting toxicities of hyperglycemia (n = 1) and stomatitis (n = 1) at 75mg. Paxalisib at 60mg was well-tolerated and adverse events were consistent with other PI3K inhibitor medicines. At the MTD (60mg), the PK profile was linear and dose-proportional with no differences in T max and elimination half-life under fed and fasted conditions. For the overall ITT population, the median progression free survival was 8.4 months (RANO) and 8.6 months (mRANO) and the median overall survival was 15.7 months. In a mITT (n = 22 patients treated with 60mg daily and ≥1 post-baseline assessment), the median PFS was 9.6 months (mRANO). Conclusions: The primary study endpoints were met; PK and safety were consistent with prior clinical experience. The MTD showed encouraging clinical activity, prolonging PFS and improving OS. Further efficacy confirmation of paxalisib 60 mg QD in newly diagnosed glioblastoma in a pivotal trial is ongoing (GBM AGILE, NCT03970447). Clinical trial information: NCT03522298.
Ethnic disparities in adverse events of chemotherapy for breast cancer: A scoping review.
Authors: Siddhi Hegde, Ruth C Carlos
Journal: Journal of Clinical Oncology (2022)

e18524 Background: Ethnic disparities may contribute to a higher symptom burden of adverse events following chemotherapy and poorer response to treatment for breast cancer. The objective was to examine the intra-group and inter-group ethnic differences in adverse effects experienced by Asian breast cancer patients undergoing chemotherapy with aromatase inhibitors or tamoxifen. Methods: A scoping review involving the Pubmed database was conducted. The search strategy included a combination of keywords and index terms related to Asians, breast cancer, CTCAE and treatment. Title, abstract and then full-text screening was performed by two reviewers. Primary research studies and systematic review articles involving female adults in peer-reviewed articles or grey literature records, of any design or date and published in English, were included. Descriptive statistics and charting was used to summarize the results. Results: Of 1765 abstracts retrieved and screened, 56 articles were ultimately included for analysis. Most articles (58.9%) studied the adverse events of tamoxifen. The majority of the studies involved Japanese patients (35.7%) followed by Chinese patients (19.6%) with an average of 8515 patients being studied per study. Only 2 studies were conducted in the US. Half the studies (50%) involved patients with TNM stage I breast cancer, postoperatively enrolled after BCS or mastectomy (71.4%). ER/PR status was reported in 58.9% of studies with an average of 494 patients being positive for either hormone receptor. HER-2 status was reported in 10 studies with an average of 53 positive HER-2 patients. 28.5% of studies involved patients with musculoskeletal adverse events following chemotherapy with aromatase inhibitors, commonly grade 3 or above (31.2%). These adverse events were arthralgia, fractures, osteoporosis or myalgia, affecting an average of 33.9% of patients in each study. 35.7% of studies involved patients with endocrinological adverse events following chemotherapy with tamoxifen. These adverse events involved menopausal symptoms, gynecological complications or endometrial cancer, affecting an average of 36.1% of patients in each study. Conclusions: Multi-level differences may contribute to the adverse events affecting Asian breast cancer patients undergoing chemotherapy with aromatase inhibitors or tamoxifen. Improving physician knowledge of ethnic disparities in adverse events occurring in Asian ethnic subgroups can help improve overall outcomes and patient adherence through a patient-centered approach.
Treatment advances in metastatic triple-negative breast cancer (TNBC): Addressing the knowledge gap.
Authors: Elizabeth Jean Heller, Keira P Smith, Sarah L Williams
Journal: Journal of Clinical Oncology (2022)

e23006 Background: The dearth of effective treatment options for patients with metastatic TNBC has enabled the rapid development of more effective treatments for this condition, but research indicates that clinicians face challenges in maintaining a working knowledge of evolving data. This study was conducted to determine if an online, case-based continuing medical education (CME)/nursing continuing professional development (NCPD)–approved activity could identify and address gaps in clinicians’ knowledge regarding the personalized care of patients with metastatic TNBC. Methods: The activity, Metastatic Triple-Negative Breast Cancer: Applying Treatment Advances to Personalized Care, chaired by Sara A. Hurvitz, MD, FACP, was made accessible starting on July 23, 2021. Learners participated in a 1-hour activity that highlighted emerging therapeutic targets in TNBC, with an emphasis on current challenges and new opportunities in the management of metastatic disease. Learners completed a repeated-pairs pre- and post-activity assessment consisting of case-based questions that gauged their ability to apply emerging data to clinical decision making. Knowledge gaps and learning gains were calculated based on percentages of learners obtaining correct responses on the pre- and post-activity assessments. Significance was assessed using a chi-squared test. Results: As of February 2, 2022, 632 clinicians had completed the activity for credit. Baseline assessment data revealed gaps in knowledge regarding emerging actionable targets and management of treatment-related adverse events (Table). The activity resulted in significant gains in knowledge and competence related to these topics, with P &lt; 0.0001 for all learning gains. Conclusions: These data indicate that a substantial knowledge gap exists regarding the latest developments in the treatment of metastatic TNBC. They also demonstrate that online, case-based CME/NCPD-approved activities can result in statistically significant improvements in clinicians’ knowledge of therapeutic advances and management of treatment-related adverse events for patients with metastatic TNBC. Acknowledgements: This activity was supported by an independent educational grant from Merck.[Table: see text]
LGG-25. The first-in-class ERK inhibitor ulixertinib (BVD-523) shows activity in MAPK-driven pediatric low-grade glioma models as single agent and in combination with MEK inhibitors or senolytics
Authors: Romain Sigaud, Lisa Rösch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Sara Najafi, Simay Ayhan, Xena F Gerloff, Nina Hofmann, Isabel Büdenbender, Kathrin I Foerster, Jürgen Burhenne, Rémi Longuespée, Cornelis M van Tilburg, David T W Jones, Stefan M Pfister, Deborah Knoerzer, Brent Kreider, Max Sauter, Kristian W Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2022)

Abstract Ulixertinib (BVD-523) is a catalytic ERK1/2 inhibitor that showed promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Pediatric low-grade gliomas (pLGG) are the most common pediatric brain tumors, with the most frequent driving alterations in the MAPK pathway. The anti-tumor activity of ulixertinib in pLGG and its potential synergism in combination with MEK inhibitors, senolytics, and chemotherapy were investigated in vitro using metabolic activity, MAPK reporter assay and high-content microscopy in pLGG-derived cell lines (DKFZ-BT66 - KIAA:BRAF fusion; BT40 - BRAF V600E mutation and CDKN2A/B deletion). The most clinically relevant combinations were further validated in vivo: 1) in zebrafish embryo models (BT40 and DKFZ-BT66 yolk sac injection) and 2) in NSG mice (BT40 orthotopic PDX) including in vivo pharmacokinetic and -dynamic analyses. Ulixertinib inhibited MAPK pathway activity in all models and reduced cell viability in the BRAF V600E mutated cell line at concentrations in the nanomolar range. In vivo pharmacokinetic and -dynamic analyses showed penetrance of the drug into mouse brain tissue and on-target activity, with concentrations above the in vitro IC50 and reduction of MAPK activity. Ulixertinib treatment slowed tumor growth and significantly increased survival in NSG mice with BT40 xenografts. Ulixertinib showed indications for anti-proliferative synergy in vitro in combination with MEK inhibitors (trametinib, binimetinib) or BH3 mimetics (navitoclax, A-1331852). Combinations with chemotherapy (carboplatin, vinblastine) were at most additive. Indications for synergy with binimetinib and navitoclax were confirmed in the zebrafish embryo models. In the NSG mouse model, the combination of ulixertinib with senolytics induced effects on tumor growth and survival comparable to ulixertinib monotherapy. Ulixertinib shows promising potential as a clinically relevant therapeutic option for the treatment of pLGG to be further investigated in upcoming clinical trials. Potential synergism with MEK inhibitors and BH3 mimetics was noted and warrants further investigation.
Adverse events self-reported by patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) treated with durvalumab (D) plus platinum-etoposide (EP) or EP in the CASPIAN study.
Authors: Mustafa Özgüroğlu, Jonathan W. Goldman, Yuanbin Chen, Marina Chiara Garassino, Nenad Medic, Helen Mann, Priti Chugh, Tapashi Dalvi, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2022)

8571 Background: The CASPIAN phase 3 study established D+EP as a global standard of care in ES-SCLC. Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to complement standard adverse event (AE) reporting in oncology trials. Here we describe patient-reported symptomatic AEs using PRO-CTCAE in CASPIAN, the first time the PRO-CTCAE tool has been piloted in SCLC research. Methods: In CASPIAN, treatment-naïve pts (WHO PS 0/1) with ES-SCLC received 4 cycles of D+EP q3w followed by maintenance D q4w until progressive disease (PD), or up to 6 cycles of EP q3w. As part of exploratory analyses, where validated local language versions were available (in English, German, Japanese or Spanish), pts were asked to complete the PRO-CTCAE by e-device at baseline, q3w during EP (in both arms), then q4w until PD, followed by day 28 post-PD, 2 months post-PD, and q8w until second progression/death. Presence/absence, frequency or severity were examined during the first 24 weeks after starting treatment across 11 AEs selected as being relevant to pts with ES-SCLC (Table). Results: In total, 164 of the 537 pts randomized to D+EP and EP in CASPIAN (31%; D+EP: 83; EP: 81) were asked to complete the PRO-CTCAE. At baseline, the PRO-CTCAE was completed by 84% of these pts in the D+EP arm and 81% in the EP arm; compliance rates &gt; 60% were achieved up to cycle 32 for D+EP and cycle 6 for EP. Examined AEs were reported by a minority of pts before starting treatment in both arms (range D+EP vs EP: 4% vs 3% for hand-foot syndrome to 34% vs 41% for dry mouth). Baseline AE rates were generally maintained in both arms up to 24 weeks after starting treatment, except for itchy skin, which showed a numerical increase from 13% at baseline to a peak of 34% at cycle 6 in the D+EP arm and 12% at baseline to a peak of 42% at cycle 8 in the EP arm; and dizziness, which showed a numerical increase from 16% at baseline to a peak of 40% at cycle 5 in the D+EP arm, while rates were maintained vs baseline in the EP arm. Most pts reporting these AEs indicated that they occurred rarely or occasionally, or were mild or moderate in severity. Conclusions: Self-reported data from pts in CASPIAN showed that the 11 AEs examined during the 24 weeks after starting treatment were reported by a minority of pts, mostly with rare or occasional occurrence, and mild to moderate severity. Rates and patterns of AEs over time were broadly similar in the D+EP and EP arms. These results complement the CASPIAN safety profile and give insight into pts’ experience of treatment. Clinical trial information: NCT03043872. [Table: see text]
Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: Preliminary results from a phase Ib study.
Authors: Chenyu Mao, Jiong Qian, Yuan Gao, Ying Liu, Tao Zhang, Jiuwei Cui, Ying Liu, Yiwei Chen, Li Zhao, Nong Xu
Journal: Journal of Clinical Oncology (2022)

e16097 Background: Sintilimab plus XELOX has been proven to be efficacious in the first line treatment of gastric cancer. Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may improve anti-tumor effect synergistically. IBI110 (anti-LAG-3 mAb) plus sintilimab (anti-PD-1 mAb) has shown preliminary antitumor activity in advance solid tumors. This phase Ib cohort study evaluated the safety and efficacy of IBI110 in combination with sintilimab and XELOX regimen for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC) in first-line setting. Methods: This phase Ib study enrolled patients with previously untreated, unresectable, locally advanced or recurrent/metastatic HER2-negative GC/GEJAC. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W plus oxaliplatin and capecitabine (XELOX) until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the safety and tolerability, and efficacy of the combination therapy. Results: As data cutoff January 20 th 2022, 18 patients were enrolled, 6 patients had locally advanced/recurrent tumors, and 12 had metastatic tumors. The median follow up time was 4 weeks (range, 0-20). The median exposure of combination therapy was 9.4 weeks (range, 3-24). Any grade TRAEs occurred in 16 pts (88.9%); most commonly white bloo4d cell count decreased (n = 6; 33.3%), neutrophil count decreased (n = 6; 33.3%), and aspartate aminotransferase increased (n = 6; 33.3%). Grade ≥ 3 TRAEs occurred in 5 pts (27.8%), including neutrophil count decreased (n = 2; 11.1%), platelet count decreased (n = 2; 11.1%) and hepatic function abnormal (n = 2; 11.1%), platelet count decreased (n = 2; 11.1%) and hepatic function abnormal (n = 2; 11.1%). Immune-mediated AEs occurred in 7 pts (38.9%); most commonly amylase increased (n = 2; 11.1%). One patient discontinued treatment because of the coronary artery disease. There were no treatment-related death. For 15 evaluable patients, the ORR and DCR were 60% (9 PR) and 100% (9 PR,6 SD), respectively. The median duration of response (DOR) and median progression free survival (PFS) were not reached. As data cutoff, 17 patients were still in treatment. Conclusions: In this phase Ib study, IBI110 in combination with sintilimab and chemotherapy was well tolerated in the first line treatment of G/GEJ AC and the clinical benefit need more follow up time to be elucidated. Clinical trial information: NCT04085185.
<i>TP53</i> pathogenic variants with low allele fraction in germline genetic testing.
Authors: Yanqin Wu, Wenzhe Fan, Miao Xue, Yiyang Tang, Suo Peisu, Bo Yang, Tanxiao Huang, Jing Zhang, Jiaping Li
Journal: Journal of Clinical Oncology (2022)

10600 Background: Blood or saliva DNA generally considered to be representative of germline genome in genetic cancer risk assessment. However white blood cells from these samples may also include somatic origin DNA due to postzygotic variation or, most commonly, clonal hematopoiesis (CH). Low variant allele fraction (VAF) found in germline genetic testing suggest the possibility of somatic variant and may lead to misinterpretation of genetic risk. TP53, of which germline pathogenic variants are associated with Li-Fraumeni syndrome (LFS), is frequently mutated in CH. This analysis investigated characteristics of TP53 pathogenic variants with low VAF. Methods: We reviewed the prevalence and distribution of TP53 pathogenic variants(PVs) detected in 11,277 advanced cancer patients who underwent clinical testing with a clinical NGS pan-cancer panel. Potential somatic PVs were defined as variants with low VAF from 10% to 35%. The VAF were evaluated in matched tumor tissue samples if available. Results: TP53 pathogenic variants were detected in 36 (0.32%) patients from blood or saliva samples, VAF between 10% and 35% were identified in 8(22.22%) patients and 7 of them were performed NGS sequencing in matched tumor tissue samples. The average VAF of tissue samples were 9.31times lower than blood or saliva samples(21.69% vs 3.88%). Conclusions: TP53 pathogenic variants with low allele fraction in blood or saliva samples indicate the possibility of somatic variant, a reduced VAF in matched tumor tissue samples may contribute to confirmation for suspicion of somatic origin.
The clinical applicability of inpatient readmissions for cancer patients.
Authors: Sandra Garcia, Ethan A Halm, Simon Craddock Lee, John W. Sweetenham, D. Mark Courtney, Arthur Hong
Journal: Journal of Clinical Oncology (2022)

e18661 Background: The 30-day rate of readmission, a standard metric for many common acute medical conditions, has also been proposed as a quality measure in cancer. However, hospitalizations for cancer patients are more heterogeneous than traditional groups (pneumonia, heart failure patients). We analyzed the pattern and timing of inpatient readmissions for a population-based sample of adults newly diagnosed with cancer. Methods: We identifiably linked adults diagnosed with cancer (2008-2018) from the UT Southwestern tumor registry to comprehensive hospital visits from a regional all-payer health exchange covering a 100-mile radius of Dallas, TX. Our primary outcome was first inpatient readmission within 30 days of discharge among patients hospitalized within 1 year of cancer diagnosis. Subsequent index periods began &gt; 30 days from index discharge to create non-overlapping readmission windows. We grouped primary diagnosis codes into 15 clinically relevant conditions, noting concordance between index and readmission diagnosis. We separately grouped hospital diagnoses deemed preventable by Medicare’s systemic therapy (chemo or immunotherapy) quality measure. We defined early readmission as occurring on days 0-7 and late as days 8-30. Results: Our cohort of 19,608 patients (49.5% female, 71.0% commercial/Medicare insurance) were most diagnosed with gastrointestinal (14.7%), breast (13.9%), and lung cancer (13.6%), with 28.9% advanced stage at diagnosis. Of those, 53.3% had received systemic therapy for their initial treatment. Patients generated 15,066 index admissions and 1,783 readmissions (11.8% 30-day readmission rate). The reason for readmission was the same as index hospitalization in 22.9% of early readmissions and 15.3% of late readmissions. Neoplasm and infection were the most common conditions; their frequencies were similar in early readmissions (12.7% and 12.8% respectively), but infections were higher in late admissions (12.0% and 15.7%). The next most common were gastrointestinal symptoms - modestly more frequent in systemic therapy patients vs. non-systemic therapy (11.4% and 9.3%); and complications of medical care, modestly more frequent in early readmissions vs. late (9.8% and 7.5%). The proportion of early readmissions for preventable diagnoses was 21.7% following receipt of systemic therapy vs 18.0% not receiving systemic therapy, and 29.2% vs. 22.5% respectively for late readmissions. Conclusions: The 30-day readmission rate in patients with cancer was 11.8% (lower than many inpatient conditions) and was usually due to reasons different than the index admission. More work is needed to validate/refine the concept of readmissions to cancer patients as an indicator of quality of care due heterogeneity of patients with cancer, the reasons they are hospitalized and rehospitalized, and relatively low rates of potential preventability.